In this project, two widely adopted non-invasive testing techniques, transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI), will be combined together to investigate the pathophysiology of adductor spasmodic dysphonia (AdSD). TMS is a direct measure of the excitability of the brain. The corresponding stimulation site, TMS hotspot, is a key node of the brain excitability network. Resting fMRI is a method used to probe the internal functional connectivity of the brain. This project will tell us how different regions of the brain interact with each other. The role of the TMS hotspot in the internal connection network has not been investigated. We are uniquely suited to pair these investigations to determine the significance of the TMS hotspot in the excitability networks of the brain of the people with AdSD, find the differences in functional connectivity, and to improve the understanding of the pathophysiology. To investigate this idea, we will first use resting state fMRI to scan people (10 people with AdSD and 10 healthy controls) to get the individual brain activity data. Next, we will use TMS to determine the area of the brain that controls the voice muscles or ‘hotspot’. Then, we will use the TMS hotspot as a seed for resting state fMRI to calculate the functional connectivity. Finally, we will compare the information of people with AdSD to that of the healthy controls. These findings will help to gain a better understanding of the abnormal central nervous system networks of this mysterious disorder. Clinically, this study will provide a reference for generating a more effective, more accurate or even custom tailored approach to treatments that target the brain that is dysfunctional. The overarching goal is to improve the quality of life of the patients with AdSD.

This grant is focused on finding a genetic cause of spasmodic dysphonia using an innovative, powerful technique called exome sequencing to screen all genes in a family affected by SD to identify a common gene mutation. To determine whether mutations in this gene contribute to additional SD and other focal/segmental primary dystonia cases, Dr. Fuchs will also screen for this gene in an additional group of volunteers with focal dystonia.

The genetic basis of most primary dystonia remains unknown and pathogenic mechanisms are poorly understood. Spasmodic Dysphonia (SD) is one of the most common forms of primary focal dystonia with a prevalence is approximately 51.7 per million. Treatment is incomplete and empiric. This grant is focused on finding a genetic cause of SD. We will use an innovative, powerful technique to screen all genes in a selected SD family to identify the causative mutation. To determine whether mutations in this gene contribute to additional SD and other focal/segmental primary dystonia cases, we will screen this gene in other familial and sporadic dystonia patients. This research will reveal a new causative gene for SD and possibly other forms of primary dystonia contributing to our understanding of disease mechanism and providing a basis for development of new therapies.

The goal of this research is to study the use of a new tool called ‘high-speed digital imaging’ to identify key components of vocal fold motion disturbance responsible for vocal spasms and strained, strangled voice quality in patients with adductor spasmodic dysphonia. The battery of tests that are currently used to clinically test vocal fold vibrations, results in invalid assessments in participants with severe dysphonia, like that of spasmodic dysphonia, due to inherent limitation of the instruments. High speed digital imaging however can capture up to 8000 frames per second; hence can be used to evaluate the small and rapid changes of vocal fold vibrations. Simultaneous laryngeal electromyographic recordings will be performed with high speed digital imaging to investigate the muscle activity responsible for the unique vibratory features observed in participants with spasmodic dysphonia. Results from this study will assist in clinical decision making regarding treatment with unilateral versus bilateral botulinum toxin injections. The findings of this study will also help investigate the much needed short-term and long-term outcomes of voice quality and vocal fold motion, following botulinum toxin treatment in patients with spasmodic dysphonia.

This proposed research will be conducted by a neurologist, Dr. Christian Kell, and is entitled, “Parametric analyses of pathology and treatment effect in spasmodic dysphonia”. This study will involve both structural and functional brain imaging in persons with spasmodic dysphonia before and after treatment with botulinum toxin injection. The purpose of this brain imaging research is to determine what parts of the brain are altered both structurally and functionally and may account for voice abnormalities in persons with spasmodic dysphonia. Because treatment with botulinum toxin is only effective for a short period and the symptoms reappear after the effects of the toxin wear off, the authors plan to identify brain regions that are abnormal in persons with spasmodic dysphonia regardless of symptoms or treatment with botulinum toxin. It is hoped that by finding both structural and functional abnormalities in the brain that are present regardless of treatment by botulinum toxin that the authors will identify the brain abnormality responsible for producing symptoms such as voice breaks in spasmodic dysphonia. Once this region is known, then future research can be aimed at changing this brain abnormality for long term treatment in SD.

In previous research, two studies found that functional differences occurred in brain activity in persons with spasmodic dysphonia (SD). One was a study conducted at the National Institute of Health by Ali et al., and published in the Journal of Speech-Language Hearing Research in 2006. The authors used Positron Emission Tomography (or PET) to measure activity in the brain and found that when persons with SD either whispered or did not have voice symptoms they had reduced brain activity in the region that receives sensory feedback from the larynx. Once the patients were treated with botulinum toxin injections this abnormality disappeared suggesting it might have been the result of symptoms rather than causing the symptoms. However, another brain abnormality was present in persons with SD both when they had symptoms and when they did not—reduced activity in the supplementary motor area (SMA). This area was identified as being involved in speech production many years ago by Dr. Wilder Penfield and colleagues in the 1940s and 1950s. Abnormalities in the SMA were present in the persons with SD even when they whispered, suggesting that this abnormality was always there. Another study by Haslinger et al., 2005 was conducted in Munich, Germany and published in the journal Neurology. These authors found reduced brain activation in the primary sensorimotor areas which was not altered by treatment. Only one study thus far has examined structural differences in the brains of persons with SD; this was conducted at the National Institutes of Health by Simonyan et al., and published in the journal Brain. These authors used high resolution structural imaging with a special technique, diffusion tensor imaging, and found reductions in the white matter tracts on the right side of the brain which were confirmed in a one post-mortem study of a brain from an SD patient.

The research to be supported by the NSDA and conducted by Kell et al., in Frankfurt Germany will be the first combined use of both functional and structural techniques in the study of the brain in persons with SD using high resolution imaging. This will involve a collaboration across two centers between Dr. Kell, a neurologist and Dr. Katrin Neuman, an otolaryngologist both at Goethe University in Frankfurt and Dr. de Jonckere, a speech language pathologist at the University of Utrecht in The Netherlands. Two years of support will be provided and this study should build on research that has already been done but provides a unique opportunity to learn which of the brain functional and structural abnormalities found by other scientists are always present in SD and should be focused on to develop long-lasting treatments for persons with SD.